The present disclosure, in some embodiments thereof, relates to pharmacology and, more particularly, but not exclusively, to methods and devices for controlled delivery by inhalation of vaporizable substances.
Over the years, many methods and devices have been developed to achieve the efficient delivery of a bioactive (pharmaceutically active) agent to a subject requiring pharmaceutical treatment. Oral ingestion, intravenous delivery and subcutaneous injection represent the two most common examples of current delivery techniques. While these techniques are generally effective, they suffer from several pharmacokinetic limitations and further often result in substantial non-compliance by patients. For example, the therapeutic benefit from conventional methods often wear off within several hours after initial dosing while the discomfort associated with injections often lead to difficulties in administration and maintenance. Even oral administration can be ineffective in cases where the bioactive agent exhibits poor bioavailability and in cases of subjects incapable of ingesting the bioactive agent due to nausea and/or vomiting.
One of the examples of a highly effective bioactive agent in dronabinol—a pure isomer of THC, or (−)-trans-Δ9-tetrahydrocannabinol, which is one of the main bioactive substances found in cannabis. Dronabinol is manufactured synthetically and marketed under the trade name Marinol®, however, the drug's use is rather limited due to its intrinsic properties, such as viscosity and hydrophobicity, which are expressed pharmaceutically in low bioavailability and incontrollable efficacy when delivered by ingestion. For example, it takes over one hour for Marinol® to reach full systemic effect compared to seconds or minutes for smoked or vaporized cannabis. Some patients accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense and untimely belated intoxication from Marinol's predetermined dosages. Many patients have said that Marinol produces a more acute psychedelic effect than cannabis, and it has been speculated that this disparity can be explained by the difficulty is controlling the amount of the bioactive agent in the subject at any given time point since this viscous hydrophobic agent, once absorbed through the GI tract, may be temporarily stored in fatty tissue before reaching the target receptors in the CNS.
While smoking is generally not recommended due to the ill effects of smoke inhalation and the low efficiency in delivery the un-combusted bioactive agent, vaporization and inhalation of the vapors of drugs suffering from low bioavailability may present a viable solution to the problems associated with injection and ingestion thereof. A partial solution is provided by some vaporization techniques aimed at delivering inhaled vaporizable bioactive agents while avoiding the respiratory hazards of smoking. While the temperature at the center of a burning cigarette is 750-800° C., vaporization can be performed at any predetermined temperature, thereby allowing vapors of the bioactive agent to form below the combustion temperature, at which pyrolytic toxic compounds are generated. It has been shown that vaporization techniques reduce formation of carbon monoxide and highly carcinogenic compounds such as polynuclear aromatic hydrocarbons (PAHs), benzene and tar.
However none of the currently known smokeless vaporization devices can be utilized for administering vaporizable bioactive agents under common pharmaceutical standards and practices, due to the inability to accurately and reproducibly control the amount that the patient inhales. The pulmonary delivery of vaporizable bioactive agents in the vapor phase varies within and between practically delivered doses due to the subjective visual estimation of the dose amount loaded by the user, repeated asynchronous inhalations from the same loaded dose, inconsistent inhalation dynamics and a time-dependent condensation of vapors onto the inner surfaces of the device. Subsequently, vaporizers in use today make proper pharmaceutical dosing and medical regimen monitoring unrealistic or impractical.
International Patent Application Publication No. WO 2008/116165 discloses systems and methods for pulmonary delivery of a drug to the respiratory system of a patient, wherein the drug is supplied in purified air at a positive pressure relative to atmospheric pressure, whereas medication available in a variety of forms is introduced in a controlled fashion into the purified air stream in aerosol, nebulized, or vaporized form.
U.S. Patent Application Publication No. 20140238423 discloses an electronic smoking article which includes a supply of a liquid material and a heater-wick element operable to wick liquid material and heat the liquid material to a temperature sufficient to vaporize the liquid material and form an aerosol. The heater-wick element comprises two or more layers of electrically resistive mesh material. This device affords no controllability and/or reproducibility in the mount being delivered to the subject.
Rabinowitz, J. D. et al. [J. Pharmacol. Exp. Ther., 2004, 309(2), p. 769-75] teach systemic delivery of pure pharmaceutical compounds without degradation products through a related process that also involves inhalation of thermally generated aerosol. According to Rabinowitz, J. D. et al., a drug is coated as a thin film on a metallic heating element and vaporized by heating the element; the thin nature of the drug coating minimizes the length of time during which the drug is exposed to elevated temperatures, thereby preventing its thermal decomposition, and the vaporized, gas-phase drug rapidly condenses and coagulates into micrometer-sized aerosol particles.
International Patent Application No. WO 2012/085919, by the present assignees, which is incorporated herein by reference, discloses inter alia metered dose inhalation devices for controlled vaporization and pulmonary delivery of bioactive agents from plant material by application of heat, wherein the device is configured to vaporize a precise amount of an agent from the plant material in a highly reproducible manner while exerting air-flow control to guarantee complete pulmonary delivery of the pre-determined dose.
Additional background art include International Patent Application Nos. WO 2008/024490 and WO 2008/024408, U.S. Pat. Nos. 6,703,418, 7,169,378, 7,987,846 and 8,235,037 and U.S. Patent Application Publication Nos. 20140100249, 20120252885, 20100168228, 20080181942, 20080176885, 20080078382, 20070072938, 20060258738 and 20060167084.